Objectives: The overall objective is to evaluate the feasibility of copper chelating strategies for the prevention and treatment of Alzheimer's disease. Specific aims: 1) To determine if copper complexing with zinc is an effective pathology-modifying therapy if initiated prior to the appearance of AD pathology. 2) To determine if zinc is effective if initiated after the onset of AD pathology. 3) To determine if copper loading accelerates the appearance of AD pathology. Plan: Copper complexing will be achieved with oral zinc sulfate, an established and safe intervention in animal models and human patients. The approach is based on experience with a more potent copper complexing agent (tetrathiomolybdate) which may be too toxic for use in human subjects. Methods: Transgenic mouse models of AD (Tg2576 and the Laferla triple transgenic mice) will be used for all of these experiments. Zinc and copper will be administered in the drinking water according to established protocols. Copper removal will be titrated by monitoring of plasma ceruloplasmin. At the end of the treatment period, spatial memory will be assessed by Morris Water Maze and brains then harvested and divided. Forebrain levels of soluble and insoluble amyloid species will be determined by ELISA and immunohistochemistry;oligomeric beta amyloid levels by western blot, copper levels by atomic absorption spectroscopy. Other proteins of interest will be measured by Western blot, and the expression of genes of interest by quantitative RT-PCR. Findings to date: 1) Brain copper and insoluble beta amyloid are reduced in a transgenic mouse model of AD when copper complexing therapy is initiated with tetrathiomolybdate (TM) prior to the age at which pathology typically appears. 2) TM treatment does not impair brain activity of copper dependent enzymes. 3) TM treatment does not impair behavioral function in mice treated for several months. 4) Zinc treatment lowers plasma ceruloplasmin and brain copper with less risk of over- chelation compared to TM. Clinical relevance: These data will be used to design clinical trials for prevention of AD in human subjects. PUBLIC HEALTH RELEVANCE: This proposal is relevant to a very important veterans'health care issue, namely the prevention and treatment of Alzheimer's disease. Alzheimer's disease is a major source of disability in late life, and afflicts vast numbers of veterans. The experiments proposed here use mice to test the possibility that therapies directed at lowering brain levels of copper will reduce the risk and perhaps slow the rate of progression of Alzheimer's disease. These studies are based on "test-tube" experiments which suggest that copper may interact with brain tissue to promote some of the changes that occur in Alzheimer's disease. Although these "test-tube" studies are convincing, it will not be possible to propose this type of treatment in human subjects unless there is confirmation of these results in an animal model, which more closely approximates the situation in human beings. We propose to use special mice which have been engineered to develop Alzheimer's-like changes in the brain. The mice will be treated with a simple, safe treatment which lowers brain levels of copper. The mouse memory and brain biochemistry will then be examined to determine if the treatment had its intended effect. If it works as expected, we will propose further studies in human subjects at risk of Alzheimer's disease. If it does not work, we will attempt to understand why not, in order to develop better treatment strategies for human patients, including aging veterans.